Is Kaposi's sarcoma the end of the OX40/OX40L axis in atopic dermatitis?

The OX40/OX40L axis entered clinical development in atopic dermatitis with a strong biological rationale and early signs of durable activity. However, as the treatment landscape evolved, questions emerged about whether the magnitude of monotherapy benefit was sufficient relative to established and emerging therapies. The discontinuation of rocatinlimab after confirmed and suspected cutaneous Kaposi's sarcoma cases, together with two cumulative cases reported in the amlitelimab program in patients with known risk factors, has changed the discussion from early promise to mechanism, risk, and therapeutic strategy. Although a causal link between OX40/OX40L modulation and Kaposi's sarcoma remains unproven, available human genetic and experimental observations make the association biologically plausible but mechanistically unresolved. The central challenge is now to determine how the axis can be targeted, in which patients, and in what therapeutic context, to maximize clinical benefit while managing risk. Rather than signaling the end of the axis in atopic dermatitis, Kaposi's sarcoma may instead mark the limits of a first-generation development strategy and the beginning of a more selective approach built around molecule design, therapeutic context, and prospective risk mitigation.